The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis, are chronic conditions with a multifactorial etiology involving interplay between a number of genetic and environmental factors. Several lines of epidemiological evidence support the hypothesis that genetic factors are particularly important in the pathogenesis of IBD and the results of seven genome-wide scans published to date have identified a number of IBD susceptibility loci. Although the disease variants within most of these loci have not been identified as of yet, the first CD-associated gene, Nod2, has been identified within the IBD1 susceptibility locus. The inheritance patterns of IBD are complex and are associated with considerable genetic heterogeneity. Thus, identification and characterization of all the genes which cause and/or modulate IBD is required to fully appreciate IBD pathogenesis and will impact substantively on the development of improved molecular diagnostic and therapeutic strategies. Additionally, better understanding of the complex genetic mechanisms leading to the onset of IBD may also provide a framework for elucidating the environmental factors which contribute to disease onset. The Mount Sinai Hospital IBD Center in Toronto has previously performed a genome-wide search for IBD susceptibility loci. The results of this analysis have revealed loci on chromosomes 19p13 and 6p to be linked to IBD. The data generated in this genome-wide search support the hypothesis that important IBD susceptibility genes lie in these chromosomal regions. These data, therefore, provide the rationale for this application as a Genetic Research Center in the context of the proposed IBDGRC. Therefore, the specific aims of this proposal are to: 1) refine the IBD susceptibility regions on chromosome 19p13 and 6p; 2) identify the susceptibility genes on chromosomes 19p13 and 6p; and 3) participate in large scale efforts to identify important susceptibility genes for IBD by contributing clinical data and biological samples in the context of the IBDGRC. The broad objective of this proposal is to make significant progress in dissecting the genetic mechanisms contributing to IBD pathogenesis. Accomplishing this will lead to the ability to identify "at risk" individuals and to intervene with targeted preventative strategies. The potential also exists for the subsequent development of improved diagnostic tests and safer and more efficacious therapies.